- Email: [email protected]
A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients
EUO-283; No. of Pages 11 E U RO P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
available at www.sciencedirect.com journal homepage: euoncology.europeanurology.com
A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients Beth Russell a,*, Fredrik Liedberg b,c, Muhammad Shamim Khan d, Rajesh Nair d, Ramesh Thurairaja d, Sachin Malde d, Pardeep Kumar e, Richard T. Bryan f, Mieke Van Hemelrijck a a
Department of Translational Oncology and Urology Research, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK;
b
Department of Urology, Skåne University Hospital, Malmö, Sweden; c Institution of Translational Medicine, Lund University, Malmö, Sweden; d Department
of Urology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; e The Royal Marsden NHS Foundation Trust, London, UK; f Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Article info
Abstract
Article history: Received 16 July 2019Received in revised form 5 September 2019Accepted September 27, 2019
Context: The complexity of bladder cancer diagnosis and staging results in delays in definitive treatment of muscle-invasive bladder cancer by radical cystectomy. Objective: This systematic review and meta-analyses aim to assess the impact of delays in radical cystectomy. Evidence acquisition: A systematic review was conducted by searching Medline and Ovid Gateway using protocol-driven search terms in August 2019, with no time limit on the studies included. The identified studies were assessed according to strict criteria and using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist and Risk of Bias in Non-randomised Studies—of Interventions (ROBINS-I) tool. Meta-analyses were conducted based on the type of delay. Randomeffect models were used whereby the presence of a delay was the exposure variable and overall survival was the outcome of interest, for which pooled hazard ratios were calculated. Evidence synthesis: Nineteen studies were eligible for inclusion (17 532 patients), of which 10 were included in the meta-analyses. A longer delay between bladder cancer diagnosis and radical cystectomy resulted in a pooled hazard ratio of 1.34 (95% confidence interval [CI]: 1.18–1.53) for overall death. For a delay between transurethral resection and cystectomy, we found a pooled hazard ratio of 1.18 (95% CI: 0.99–1.41) for overall death. A pooled hazard ratio of 1.04 (95% CI: 0.93–1.16) was calculated for a longer delay between neoadjuvant chemotherapy and radical cystectomy. Conclusions: A delay in radical cystectomy after diagnosis was found to have a significantly detrimental effect on overall survival for bladder cancer patients. However, there was huge heterogeneity in how a delay was defined. Patient summary: In this review, we investigated the effect of a delay in radical treatment on survival. This review highlights the importance of scheduling radical cystectomies in a timely manner whilst monitoring factors such as comorbidities and scheduling, in order to treat patients requiring radical cystectomy without delay. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Gianluca Giannarini Keywords: Bladder cancer Radical cystectomy Delay Survival
* Corresponding author. Department of Translational Oncology and Urology Research, Research Oncology, King’s College London, 3rd Floor Bermondsey Wing, Guy’s Hospital, Great Maze Pond, London, UK. E-mail address: [email protected] (B. Russell).
https://doi.org/10.1016/j.euo.2019.09.008 2588-9311/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 2
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
1.
Introduction
Bladder cancer (BC) is the ninth most common cancer worldwide, with around 550 000 new cases in 2018 [1]. Five-year disease-specific survival rates are 77% in the USA and around 68% in Europe [2,3]. As many as 50% of muscle-invasive BC (MIBC) patients die from metastatic disease within 3 yr of diagnosis despite radical cystectomy (RC) [4]. A delay in radical treatment is thought to contribute to the risk of metastases and therefore decreased survival [5]. Thus, for selected patients with high-risk non– muscle-invasive BC (NMIBC) or MIBC who require RC as primary treatment, the European Association of Urology (EAU) recommends RC within 3 mo of diagnosis [6,7]. However, previous studies have demonstrated both increased and decreased survival associated with delay in RC. The impact of this delay on survival outcomes has recently been identified as one of the top 10 unanswered research questions by BC patients and health care professionals, thus highlighting the importance of studying this topic [8]. In addition to a delay between the first symptoms and a BC diagnosis, there are several mechanisms by which radical definitive treatment may be delayed for BC patients [9]. Patients may not be fit enough for immediate surgery and so require treatment of comorbidities, or may be referred from primary care physicians or urology units to different hospitals for surgery [10]. Furthermore, seeking a second opinion and the need for additional investigations, particularly up to the date of imaging, may also delay RC. The most recent systematic review of the effects of delays in RC was conducted by Fahmy et al [5] in 2006 and included 13 studies published between 1965 and 2006. Whilst they concluded that a delay in radical treatment was associated with a worse outcome, they did not quantify this effect. Given that the past 10 yr has seen a number of changes to the treatment of MIBC patients by RC (eg, centralisation of RC to larger hospitals, neoadjuvant chemotherapy [NAC], robotic cystectomy, and prehabilitation), we aimed to reassess this question by reviewing more recent studies, quantifying the effect of a delay on survival using meta-analyses, and establishing a standardised definition of a delay in radical treatment. 2.
Evidence acquisition
2.1.
Search strategy and inclusion criteria
The research question, search strategy, and inclusion and exclusion criteria were defined by a protocol (see the Supplementary material). Studies were identified by conducting searches of Medline (PubMed) and Ovid Gateway (Embase and Ovid) using the following search terms: “bladder” and/or “tumours” and/or “cancer”, “survival” or “death” and “delay” or “referral”. Initially, the titles of the studies were screened to identify the relevant studies. The abstracts and subsequently full texts were then carefully read to identify those that met the inclusion criteria. We used the following inclusion criteria: a randomised controlled study, an observational study, or an original
article (no commentaries, author’s replies, reviews, supplements, editorials, or systematic reviews), which was written in English, included patients who have undergone RC for BC, reported outcomes in the form of overall survival and/or BCspecific survival and/or 5-yr survival estimates, was certainly not looking at an alternative treatment regime to surgery, and definitely included at least one category of delay between diagnosis of BC and definitive treatment with RC. There were no criteria of selection based on the date of publication to include all results possible in the meta-analysis. Clinical characteristics, number of study participants, country of study, and delay definitions were extracted from each study. The search was carried out in August 2019. Screening of titles, abstracts, and full texts was carried out by B.R. and M.V.H. There were no disagreements between authors. B.R. extracted the data from the chosen articles. 2.2.
Meta-analyses
Studies were deemed suitable for inclusion in the metaanalysis if they reported both hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival as an outcome. The studies were categorised based on the type of delay investigated (total delay from diagnosis of BC to RC, delay between transurethral resection of bladder tumour [TURBT] and RC, and delay between termination of NAC and RC), and each category was meta-analysed separately. Randomeffect models were used whereby the presence of a delay was the exposure variable and overall survival was the outcome of interest (measured using the adjusted HRs from each study), for which pooled HRs were calculated. For each meta-analysis, sensitivity analyses were performed by removing each individual study, one at a time, to detect any changes in the overall result. I2 scores were also reported to define the severity of heterogeneity. 2.3.
Quality assessment of studies
All included studies were classified as observational; therefore, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 22-item checklist was used to assess the quality of the articles [11]. A risk of bias assessment was also carried out using the Risk of Bias in Non-randomised Studies—of Interventions (ROBINS-I) tool [12]. The review was also conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to enhance the quality of the results and was registered on PROSPERO (registration number: CRD42018118936). 2.4.
Evidence synthesis
Our search strategy identified 399 articles (Fig. 1). From these, 38 duplicates were excluded; a further 324 articles were excluded based on the inclusion criteria outlined above following title and abstract review. The full texts of 37 articles were then read, of which 19 were deemed suitable for inclusion (Table 1).
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
3
Fig. 1 – PRISMA flow diagram for selection of studies in systematic review and meta-analysis. NAC = neoadjuvant chemotherapy; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RC = radical cystectomy; TURBT = transurethral resection of bladder tumour.
All the remaining 19 articles were observational studies published between 1991 and 2019. The sample sizes ranged from ten to 2738, with a total of 17 532 patients who underwent RC in the studies. Eight of the studies were conducted in the USA, four in Canada, two in the UK, two in Germany, and one each in The Netherlands, Sweden, and New Zealand. 2.5.
Quality of studies
Assessment of each study using the STROBE checklist highlighted studies of particularly high or poor quality
(Supplementary Table 1). Most studies were of good quality according to the checklist; however, the studies by Munro et al [13] and Kahokehr et al [14] appeared to satisfy the fewest checklist items and, therefore, were deemed to have lower quality than the other studies. The studies by Gulliford et al [15], Williams et al [16], Santos et al [17], Mahmud et al [18], Kulkarni et al [19], Audenet et al [20], and Boeri et al [21] were considered to be of high quality. A risk of bias assessment revealed that all the studies were considered to have either a low or a moderate risk of bias (Supplementary Table 2) [12]. The impact of this variation was assessed through our leave one out sensitivity analyses
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 4
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Table 1 – Descriptive data of the studies included in the systematic review. Study ID
Reference
Authors (date of publication)
No. of participants who underwent RC and included in analysis
T stage
Pathological N stage
1 2 3 4 5 6 7 8 9
[22] [15] [16] [13] [23] [28] [14] [24] [20]
Lee et al (2006) Gulliford et al (1991) Williams et al (2017) Munro et al (2010) Gore et al (2009) Nielsen et al (2007) Kahokehr et al (2016) Liedberg et al (2005) Audenet et al (2019)
214 10 2738 96 441 592 43 141 2227
NA NA cT2-T4 NA cT2 cT2-T4 cT0-T4 cT0-T4 cT2-T4a
NX/N0/N+ NA NA NA N0 N0/N+ N0-N2 (clinical stage only) NX/N0/N+ cN0 pN0/N+
USA UK USA UK USA USA New Zealand Sweden USA
153 1782 1271 189 1633 1592 278 2397 1509 226
cT2-T4 cT2-T4 NA cT2-T4 NA NA NA NA cT2 cT2-T4
N0/N+ N0/N+ NA N0/N+ NA NA N0/N+ NX/N0/N+ N0 N0-N3
USA The Netherlands Canada Germany Canada Canada Germany Canada USA USA
Studies included in meta-analyses [31] Alva et al (2012) c 10 [30] Bruins et al (2016) b 11 [17] Santos et al (2015) a 12 13 [25] May et al (2004) a [26] Fahmy et al (2008) a 14 [18] Mahmud et al (2006) b 15 [27] Jager et al (2010) b 16 17 [19] Kulkarni et al (2009) b [29] Chu et al (2019) b,c 18 19 [21] Boeri et al (2019) c
Country of study
cT/cN = clinical T/N stage; NA = not applicable; NAC = neoadjuvant chemotherapy; RC = radical cystectomy; TURBT = transurethral resection of bladder tumour. Included in meta-analysis for total delay between diagnosis of bladder cancer and RC. b Included in meta-analysis for delay between TURBT and RC. c Included in meta-analysis for delay between NAC and RC. a
(see below). Furthermore, only six of the studies stated whether ethical approval or approval to use the respective databases was obtained. 2.6.
Delay and survival
The results from the 19 studies varied greatly, as did the methodology and therefore interpretation of the results. There was a variation in the type of delay investigated within the pathway from diagnosis of BC to RC (as shown in Tables 2 and 3). Ten of the studies evaluated the total delay between diagnosis of BC and RC, of which one included patients who received NAC [13,15–17,20,22–26]. Seven of the studies assessed the effect of the delay between TURBT and RC; all but one of these looked specifically at the most recent TURBT, whilst Jäger et al [27] analysed a delay in RC in the context of NMIBC and used the first TURBT as the start date for analysis [14,18,19,28–30]. Two of these studies carried out additional analyses for patients who received NAC. Two studies investigated only the delay between NAC and RC [21,31]. 2.7.
Delay between diagnosis of BC and RC
There was disparity in the number of days or months at which a significant association between delay and survival was identified (Tables 2 and 3). Several studies incorporated tumour stage into their analysis, and many concluded that this factor had a significant impact on the results. Overall, four of the studies found a significant association between delay from diagnosis to RC and survival (Tables 2 and 3) [17,22,23,26].
2.8.
Delay between TURBT and RC
Kulkarni et al [19] used cubic spline regression analysis to recommend an ideal wait time of 40 d. Audenet et al [20] first looked at the time from TURBT and RC as a continuous variable, and found no significant association with overall survival. They then looked at this time interval in deciles and concluded no significant cut-off point in predicting worse overall survival up to the ninth decile (222 d). Overall, four of the studies found an association between the delay in RC after TURBT and survival (Tables 2 and 3) [18,19,27,29]. 2.9.
Use of NAC
Five studies included separate analyses for patients who received NAC to determine whether a delay in time after NAC to RC is associated with survival [20,21,29,30]. Neither studies by Alva et al [31] or Bruins et al [30] found a significant association between a delay in RC after NAC and survival. Other studies included NAC patients in the overall analyses, but Kahokehr et al [14] looked at the time period between the last cycle of treatment and surgery and its effect on survival. This study concluded a paucity of significance between survival and delay when also including patients who received NAC. Chu et al [29] and Boeri et al [21] both investigated the time from the last documented infusion with NAC and RC. Both studies found that a longer delay between NAC and RC significantly increased the risk of overall death. Audenet et al [20] looked at the time from diagnosis to initiation of NAC and concluded that patients with a delay of 6 mo or more had significantly worse overall survival.
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 5
E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Table 2 – Delay definitions and summary of results for studies included in systematic review only. Study Reference ID
Authors (yr of publication)
Delay definition
Delay cut-off
Results
Median delay Delay between diagnosis of BC and RC [22] Lee et al (2006) 1
Conclusions
Diagnosis of BC to RC
93 d
61 d
Referral to 1 st treatment Diagnosis of BC to RC 1 st clinic to radiotherapy or RC Diagnosis of BC to RC
84 d
NA
84 d
NA
84 d
NA
28–56, 56–84, 84–168, & 168 d
NA
Diagnosis of BC to RC
60 d
49 d
TURBT to RC
90 d
55 d
No change in survival when there was a delay between the most recent TURBT and RC.
Studies that were also inclusive of NAC patients 7 [14] Kahokehr et al (2016) TURBT to RC
31 d
Mean = 62 d
From diagnosis to initiation of NAC: 56 d From diagnosis to RC: 183 d
From diagnosis to initiation of NAC: 39 d From initiation of NAC to RC: 112 d
No change in survival when there was a delay between TURBT and RC. No significant change in overall survival when there was an increase in time from diagnosis to surgery with or without the use of NAC. An increase in time from diagnosis to chemotherapy (56 d) was associated with an increased risk of pathological upstaging (OR = 1.27, 95% CI: 1.02–1.59).
2
[15]
Gulliford et al (1991)
3
[16]
Williams et al (2017)
4
[13]
Munro et al (2010)
5
[23]
Gore et al (2009)
8
[24]
Liedberg et al (2005)
Delay between TURBT and RC 6 [28] Nielsen et al (2007)
9
[20]
Audenet et al (2019)
Diagnosis of BC to RC
BC = bladder cancer; CI = confidence interval; NA = not TURBT = transurethral resection of bladder tumour.
2.10.
applicable;
Those delayed longer than 93 d were at a 96% increased risk of death from any cause and a 112% increased risk of death from BC compared with those with a cystectomy delay of 93 d. No change in survival when first treatment was delayed. No change in overall or cancer-specific survival when RC was delayed. No change in survival when radiotherapy or RC was delayed. A delay of >12 wk between diagnosis and RC was associated with a 201% increased risk of all-cause and disease-specific mortality (p = 0.003). No change in disease-specific survival when there was a delay between diagnosis and RC.
NAC = neoadjuvant
Reasons for delays
Several studies included reasons as to why treatment with RC was delayed. The studies by Lee et al [22] and Alva et al [31] suggested that scheduling was one of the main causes for delay in surgical treatment, with as many as 46% of the cohort in the study by Lee et al [22] were affected by this. Other causes included seeking multiple medical opinions, social issues, and misdiagnosis. Both Lee et al [22] and Gore et al [23] suggested that reluctance to treat and patients’ comorbidities also contributed to delays, with two other studies also reaching the same conclusion. According to Gore et al [23], comorbidities affected the delay since patients had to wait to be transferred to centres better equipped to deal with the burden of care, as well as requiring more time for medical optimisation. Chu et al [29] ran a separate logistic regression analysis to identify factors affecting whether the patients experienced a delay or not. They concluded that living in a highpoverty neighbourhood or rural area, and being transferred to another care provider between TURBT and RC were
chemotherapy;
OR = odds
ratio;
RC = radical
cystectomy;
associated with increased RC delays. Conversely, no patient, provider, or health system factors were found to be independently associated with RC delays in the NAC cohort. Boeri et al [21] also looked into factors associated with a delay and found that patients with a higher Charlson Comorbidity Index (1) were associated with longer median time to cystectomy. 2.11.
Gender disparities
Most of the studies investigated gender in terms of the varying delays experienced by patients and/or how survival was affected by delay between genders. Fahmy et al [26] additionally found a significant association with an increased median delay (defined as the period between visiting a family practitioner and seeing a urologist) in women when compared with men. They also concluded that men were more likely to experience a delay of <20 d than women for the same time period. In contrast, Chu et al [29] identified male gender as an independent characteristic associated with RC delays.
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 6
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Table 3 – Delay definitions and summary of results for studies included in the meta-analyses. Study ID Reference
Authors (yr of publication)
Delay definition
Delay cut-offa
Results Median delay
Delay between diagnosis of BC and RC [17] Santos et al (2015) 12
Diagnosis of BC to RC (including referral delay)
Direct/indirect referral
30 d
13
[25]
May et al (2004)
Diagnosis of BC to RC 90 d
55 d
14
[26]
Fahmy et al (2008)
Diagnosis of BC to RC 24, 24–84, 85 d
93 d
Delay between TURBT and RC [18] Mahmud et al (2006) TURBT to RC 15
84 d
33 d
16
[27]
Jager et al (2010)
TURBT to RC
120 d
122 d
17
[19]
Kulkarni et al (2009)
TURBT to RC
90 d
50 d
18
[29]
Chu et al (2019)
TURBT to RC
From TURBT to RC: 84 d
NA
11
[30]
Bruins et al (2016)
TURBT to RC
60 d
No NAC: 50 d NAC: 133 d
NAC to RC
28–84 d
From initiation of NAC: 117 d From termination of NAC: 49 d 53 d
Delay between NAC and RC 10 [31] Alva et al (2012)
19
[21]
Boeri et al (2019)
NAC to RC
70 d
18
[29]
Chu et al (2019)
TURBT to RC and NAC to RC
From completion of NA NAC to RC: 77 d
Conclusions
Patients indirectly referred to a urologist after a first GP visit experienced a 29% increased risk of mortality compared with those directly referred (95% CI: 1.10–1.52). No change in overall survival when RC was delayed, though this relationship was borderline significant (HR = 1.62, 95% CI: 0.99–2.66). A delay of <25 or >84 d between visiting the family physician and RC was associated with a 230% and a 40% increased risk of death from any cause, respectively (95% CI: 1.4–3.9 and 1.1–1.8, respectively). A delay of >12 wk between the most recent TURBT and RC is associated with a 20% increased risk of dying from any cause (95% CI: 1.00–1.50). A delay of >120 d between the first TURBT and RC was associated with significantly worse 5-yr cancer-specific survival compared with those with a delay of <120 d (77% vs 86%). A delay of >90 d between TURBT and RC was associated with an increased risk of death from all causes compared with those with a delay of 90 d (HR = 1.001, 95% CI: 1.000– 1.002). This represents an increased risk of death for each day a patient waits for an RC. Overall survival was significantly reduced in patients who did not receive NAC and were aged <80 yr (HR: 1.39, p < 0.05). No change in survival when there was a delay between diagnosis of BC and RC. No change in survival when there was a delay between the termination of NAC treatment and RC or between the initiation of NAC and RC. Time to cystectomy of >10 wk was associated with adverse overall survival and bladder cancer–specific survival. Patients who received NAC and whose RC was delayed suffered significantly higher mortality over time.
BC = bladder cancer; CI = confidence interval; GP = general physicians; HR = hazard ratio; NA = not applicable; NAC = neoadjuvant chemotherapy; RC = radical cystectomy; TURBT = transurethral resection of the bladder tumour. a The cut-off point for each study is the one from which the HRs and 95% CIs were taken for the meta-analyses.
2.12.
Meta-analyses
The delay definitions for each study are outlined in Fig. 2, and these were considered the exposure variables in the meta-analyses. When studying the delay between diagnosis of BC and RC, the meta-analysis revealed a pooled HR of 1.34 (95% CI: 1.18–1.53) for overall survival (Fig. 3). Sensitivity analyses by the removal of individual studies did not identify any significant changes in the results. The I2 test was 0.0%, suggesting a very low level of heterogeneity between the studies. For a delay between TURBT and RC, the meta-analysis calculated a pooled HR of 1.18 (95% CI: 0.99–1.41) for overall survival (Fig. 3). The removal of
individual studies in the sensitivity analyses did not significantly change the overall result for all studies except for the study by Kulkarni et al [19]. Removal of this study resulted in a pooled HR of 1.26 (95% CI: 1.06–1.51). The I2 test was 72.9%, indicating a relatively high level of heterogeneity between the studies. For a delay between NAC and RC, the meta-analysis calculated an HR of 1.04 (95% CI: 0.93-1.16) for overall survival (Fig. 3). Sensitivity analyses by the removal of individual studies did not identify any significant changes in the results. The funnel plots for the meta-analyses appear to suggest a slight publication bias in the direction of worse survival associated with a delay (Supplementary Fig. 1).
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Fig. 2 – Definitions for total delay (diagnosis of BC to RC) and delay between TURBT and RC. (A) The number of days used by each study to define a total delay in patients receiving treatment by radical cystectomy. The study by Santos et al [17] is not included, as the delay was defined as “direct” or “indirect” referral, and was therefore not able to be depicted on the diagram. (B) The number of days used by each study to define a delay between TURBT and RC. The study by Kulkarni et al [19] is not included in the diagram, as delay was treated as a continuous variable. (C) The number of days used by each study to define a delay between NAC and RC. The study by Alva et al [31] is not included in the diagram, as delay was treated as a continuous variable. BC = bladder cancer; NAC = neoadjuvant chemotherapy; RC = radical cystectomy; TURBT = transurethral resection of bladder tumour.
3.
Discussion
This is the first study to estimate the pooled effect on survival from a delay in RC using results from multiple
7
studies. Our findings suggest that a longer period of time between diagnosing BC and undergoing RC negatively impacts the overall survival of patients and is influenced by many factors. This review also highlights that despite the 12-wk EAU guideline, many centres do not adhere to this and/or choose to analyse their data using different cut-offs. We, therefore, need to work out a safe cut-off and ensure that there is a consensus in how delay is defined. Whilst the pooled meta-analysis for a delay between TURBT and RC was not significant, removal of the study by Kulkarni et al [19] resulted in a significant result. Interestingly, Kulkarni et al [19] treated delay as a continuous variable, which may be a contributing factor to the reasons why this result varied from the others. The previous systematic review conducted by Fahmy and colleagues [5] concluded that the majority of studies confirmed that delays were associated with worse outcomes. Similar to the current study, Fahmy and colleagues [5] found that there was a variation in the type of delay investigated and the period of time used to define a delay. A major advantage of the current study compared with the previous review is the inclusion of meta-analyses to quantify the impact that delays in RC may have on overall survival. Furthermore, most of the studies included were published after 2006, therefore incorporating data that were not available at the time of the previous review. Comorbidities, scheduling delays, and reluctance to be treated were all suggested as substantial contributors to treatment delay [14,17,22,23]. Of these three factors, scheduling delays should be both manageable and avoidable. However, the so-called “distance bias effect”, suggesting improved survival for patients referred to a distant higher-volume hospital for RC [32], also generates prolonged treatment delay—“a volume delay paradox” that needs to be handled in clinical practice [33]. Nevertheless, awareness of this phenomenon could still motivate hospitals to have patients treated in a timely manner and subsequently improve outcomes. Comorbidities and reluctance to treat are much harder variables to manage; it is crucial that clinicians are aware of their impact on treatment delay and, hence, survival. Accessible patient information and signposting to peer support groups can help patients address their reluctance to be treated, by allowing them to receive encouragement and information directly from other people who have had an RC. Administering NAC to improve survival after RC also adds complexity to the scheduling process before RC, and delays in the start of such preoperative chemotherapy by more than 8 wk have been associated with pathological upstaging [20]. The studies included in this review found mixed results between a delay in RC and survival in patients who received NAC, with the meta-analysis finding no significant association. It is known that NAC prior to RC significantly reduces patient mortality [34,35]; however, from the current data, it is not possible to identify whether the lack of an effect of delay on mortality in those who received NAC is due to the potential beneficial effects of NAC. Furthermore, patients who receive NAC tend to be younger with fewer comorbidities and are therefore already at a survival advantage [36].
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 8
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Fig. 3 – Forest plots. (A) Forest plot for total delay between diagnosis of bladder cancer and radical cystectomy. (B) Forest plot for delay from TURBT to RC. (C) Forest plot for delay between termination of NAC and radical cystectomy. CI = confidence interval; HR = hazard ratio; NAC = neoadjuvant chemotherapy; RC = radical cystectomy; TURBT = transurethral resection of the bladder tumour.
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Most of the studies investigating disparities in delay time and/or survival amongst men and women did not find any significant association. This suggests that both males and females are equally as likely to experience a delay and are both similarly affected by delays in RC; although delays in the referral of symptomatic female patients from primary care to secondary care may contribute to a stage migration at eventual diagnosis, there is no such disparity in secondary care [37]. Some studies (eg, those by Gulliford et al [15] and Munro et al [13]) did not limit their exposure to include only RC, and additionally included radical radiotherapy and systemic chemotherapy as treatment options. Therefore, we could not be certain that the delays associated with the risk of survival were accurate for delays in RC, and these studies were subsequently excluded from the meta-analysis. Despite the 3-mo guideline set by the EAU, it is clear from this review that not all centres are adhering to this guideline and many of the studies available use varied cut-off points for their analysis. There is also uncertainty as to the definition of the starting point for delay, for example, at onset of symptoms, at diagnosis, at initial TURBT, or after termination of NAC. For example, the 40 d suggested by Kulkarni et al [19] refers to the delay between TURBT and cystectomy in an era before NAC was widespread. However, the development of rapid access diagnostic pathways for patients with macroscopic haematuria strongly suggest the haematuria referral date as the starting point for delay and facilitate national guideline recommendations on treatment delay [38]. Across all malignancies, BC patients experience the longest delays from symptom onset to diagnosis [39], and it is therefore advisable to strive toward a short delay between haematuria clinic assessment and RC (especially when one considers the psychological effects of delaying RC) [40]. Equally, one may also argue that the first TURBT date is a clear, measureable time point to start timing a delay from. However, the results from this study suggest that a longer delay from this time point may not impact delay significantly. Possible reasons for this may be the debulking of the tumour during the procedure or the variation in the cut-offs used to define a delay. 4.
Strengths and limitations
Many of the studies included were large cohort studies that could generally be considered to have high external validity. However, the data used for the study by Alva and colleagues [31] were obtained from a single centre and, consequently, as stated by the authors, are limited in terms of generalisability. Tumour stage was found to be a major influential factor for prognosis and was included in most study analyses. However, the study by Santos et al [17] did not adjust for stage, which is a major limitation of this study. Alternatively, patients with more advanced tumour stages might be prioritised in scheduling ahead of patients with less advanced asymptomatic tumours [37,41]; thus, tumour stage might affect the exposure variable in cohort studies
9
investigating treatment delays. Chu et al [29] additionally identified positive lymph node status as a strong predictor of increased mortality amongst patients who received NAC. Therefore, studies that failed to report pathological N stage are limited. This review did not acquire enough studies to be able to perform subgroup analyses by N or T stage. As mentioned, these variables can have an impact on survival; therefore, this is a limitation to the current meta-analyses. Another limitation is the paucity of data for fundamental variables in some studies; for example, Nielsen et al [28] did not collect information on pre-existing comorbidities, potentially major contributory factors to prolonged delays. The most prominent limitation in this review was the heterogeneity between studies due to the variation in the definition of delay, as well as the demographic composition of the cohorts and the endpoints of interest. This made comparing these different studies challenging (as noted by Mahmud et al [18]). The heterogeneity of the studies is highlighted in the relatively large I2 scores reported for the meta-analyses. 5.
Future research
Results from these studies have shed light on the complexity of the relationship between RC delays and survival. We therefore recommend that future studies consider this complexity when planning data capture. In the setting of the guideline-recommended treatment of NAC and RC, we recommend the following definitions for periods of delay to be used by future studies:
1 Symptom onset to primary care referral for urological assessment 2 Referral for urological assessment to actual urological assessment 3 Initial urological assessment to TURBT 4 TURBT to commencement of NAC 5 Commencement of NAC to completion of NAC 6 Completion of NAC to RC Not all studies will be established to capture all time points, but the relevant components thereof are to be recommended. Furthermore, awareness of all the components of total delay may highlight individual elements where pathways can be improved and/or optimised. 6.
Conclusions
This systematic review has updated the data and knowledge regarding delays in RC and patient survival, whilst the addition of the meta-analysis enabled quantification of this pooled effect for the first time. The BC diagnostic and treatment pathway is complex, involving generally elderly patients with multiple comorbidities; hence, some delays may be unavoidable. However, there still remains a lack of consensus as to what period of delay is acceptable before negatively impacting survival; hence, more work is needed to
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 10
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
answer what has recently been identified as one of the top 10 unanswered questions in BC. Notwithstanding, we have demonstrated that a longer delay from BC diagnosis to RC is associated with significantly worse survival. This current review has also highlighted the lack of standardisation regarding how delays are defined, and therefore using more fixed, measurable time points is of interest for future studies. In conclusion, BC patients who require RC should be treated without delay so as to maximise survival. Several factors impact delay, such as other medical conditions and scheduling, and these must be monitored by medical practitioners in order to minimise unnecessary delays and maximise survival.
[5] Fahmy NM, Mahmud S, Aprikian AG. Delay in the surgical treatment of bladder cancer and survival: systematic review of the literature. Eur Urol 2006;50:1176–82. [6] Babjuk M, Böhle A, Burger M, et al. Guidelines on non-muscleinvasive bladder cancer (Ta, T1 and CIS). European Association of Urology 2015. [7] Witjes J, Bruins M, Cathomas R, et al. EAU guidelines: muscleinvasive and metastatic bladder cancer.
https://uroweb.org/
guideline/bladder-cancer-muscle-invasive-and-metastatic/#72019 [8] Bessa A, Maclennan S, Enting D, et al. Consensus in bladder cancer research priorities between patients and healthcare professionals using a four-stage modified Delphi method. Eur Urol 2019;76:258–9. [9] Williams SB, Hudgins HK, Ray-zack MD, et al. Systematic review of factors associated with the utilization of radical cystectomy for
Author contributions: Beth Russell had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
bladder cancer. Eur Urol Oncol 2019;2:119–25. [10] Tomaszewski JJ, Handorf E, Corcoran AT, et al. Care transitions between hospitals are associated with treatment delay for patients with muscle invasive bladder cancer. J Urol 2014;192:1349–54.
Study concept and design: Russell, Van Hemelrijck.
[11] Vandenbroucke JP, Von Elm E, Altman DG, et al. Strengthening the
Acquisition of data: Russell.
Reporting of Observational Studies in Epidemiology (STROBE):
Analysis and interpretation of data: Russell, Van Hemelrijck.
explanation and elaboration. Epidemiology 2007;18:805–35.
Drafting of the manuscript: Russell. Critical revision of the manuscript for important intellectual content: Russell, Liedberg, Khan, Nair, Thurairaja, Malde, Kumar, Bryan, Van Hemelrijck.
[12] Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:i4919. [13] Munro NP, Sundaram SK, Weston PMT, et al. A 10-year retrospective
Statistical analysis: Russell.
review of a nonrandomized cohort of 458 patients undergoing
Obtaining funding: Van Hemelrijck, Kumar.
radical radiotherapy or cystectomy in Yorkshire, UK. Int J Radiat
Administrative, technical, or material support: Van Hemelrijck.
Oncol 2010;77:119–24.
Supervision: Van Hemelrijck, Liedberg, Bryan. Other: None.
[14] Kahokehr A, Glasson J, Studd R. Surgical waiting time for radical cystectomy: a New Zealand experience. ANZ J Surg 2016;86:1042–5. [15] Gulliford MC, Petruckevitch A, Burney PGJ. Survival with bladder
Financial disclosures: Beth Russell certifies that all conflicts of interest,
cancer, evaluation of delay in treatment, type of surgeon, and
including specific financial interests and relationships and affiliations
modality of treatment. BMJ 1991;303:437–40.
relevant to the subject matter or materials discussed in the manuscript
[16] Williams SB, Huo J, Dafashy TJ, et al. Survival differences among
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
patients with bladder cancer according to sex: Critical evaluation of
stock ownership or options, expert testimony, royalties, or patents filed,
radical cystectomy use and delay to treatment. Urol Oncol Semin
received, or pending), are the following: None.
Orig Investig 2017;35:602, e1–9.
Funding/Support and role of the sponsor: This work was supported by Guy’s and St Thomas’ Charity, and the Royal Marsden Cancer Charity. Acknowledgements: We would like to thank Fight Bladder Cancer for its support and input into this review.
[17] Santos F, Dragomir A, Kassouf W, Franco E, Aprikian A. Urologist referral delay and its impact on survival after radical cystectomy for bladder cancer. Curr Oncol 2015;22:e20–6. [18] Mahmud SM, Fong B, Fahmy N, Tanguay S, Aprikian AG. Effect of preoperative delay on survival in patients with bladder cancer undergoing cystectomy in Quebec: a population based study. J Urol 2006;175:78–83.
Appendix A. Supplementary data
[19] Kulkarni GS, Urbach DR, Austin PC, Fleshner NE, Laupacis A. Longer wait times increase overall mortality in patients with bladder
Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j. euo.2019.09.008.
cancer. J Urol 2009;182:1318–24. [20] Audenet F, Sfakianos JP, Waingankar N, et al. A delay 8 weeks to neoadjuvant chemotherapy before radical cystectomy increases the risk of upstaging. Urol Oncol Semin Orig Investig 2019;37:116–22. [21] Boeri L, Soligo M, Frank I, et al. Delaying radical cystectomy after neoadjuvant chemotherapy for muscle-invasive bladder cancer is
References
associated with adverse survival outcomes. Eur Urol Oncol [1] World Cancer Research Fund. Bladder cancer statistics. https:// www.wcrf.org/dietandcancer/cancer-trends/ bladder-cancer-statistics2018 [2] European Network of Cancer Registries. Bladder cancer (BLC) factsheet.
https://www.encr.eu/sites/default/files/factsheets/
ENCR_Factcheet_Bladder_Cancer_2016.pdf2016 [3] American Cancer Society. Survival rates for bladder cancer. https:// www.cancer.org/cancer/bladder-cancer/ detection-diagnosis-staging/survival-rates.html2016 [4] Wu X-R. Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 2005;5:713–25.
2019;2:390–6. [22] Lee CT, Madii R, Daignault S, et al. Cystectomy delay more than 3 months from initial bladder cancer diagnosis results in decreased disease specific and overall survival. J Urol 2006;175:1262–7. [23] Gore JL, Lai J, Setodji CM, Litwin MS, Saigal CS. Mortality increases when radical cystectomy is delayed more than 12 weeks: results from a SEER Medicare analysis. Cancer 2009;115:988–96. [24] Liedberg F, Anderson H, Mansson W. Treatment delay and prognosis in invasive bladder cancer. J Urol 2005;174:1777–81. [25] May M, Nitzke T, Helke C, Vogler H, Hoschke B. Significance of the time period between diagnosis of muscle invasion and radical
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
cystectomy with regard to the prognosis of transitional cell carcinoma of the urothelium in the bladder. Scand J Urol Nephrol 2004;38:231–5. [26] Fahmy N, Kassouf W, Jeyaganth S, et al. An analysis of preoperative delays prior to radical cystectomy for bladder cancer in Quebec. CUAJ 2008;2:102–8.
11
following radical cystectomy in patients with muscle-invasive bladder cancer. Urology 2018;114:87–94. [34] Advanced Bladder Cancer Overview Collaboration. Neoadjuvant chemotherapy for invasive bladder cancer. Cochrane Database Syst Rev 2005;2:CD005246. [35] Sherif A, Holmberg L, Rintala E, et al. Neoadjuvant cisplatinum
[27] Jäger W, Thomas C, Haag S, et al. Early vs delayed radical cystectomy
based combination chemotherapy in patients with invasive bladder
for “high-risk” carcinoma not invading bladder muscle: delay of
cancer: a combined analysis of two Nordic studies. Eur Urol
cystectomy reduces cancer-specific survival. BJU Int 2011;108(8 Pt 2), E284–8. [28] Nielsen ME, Palapattu GS, Karakiewicz PI, et al. A delay in radical cystectomy of &3 months is not associated with a worse clinical outcome. BJU Int 2007;100:1015–20. [29] Chu AT, Holt SK, Wright JL, et al. Delays in radical cystectomy for muscle-invasive bladder cancer. Cancer 2019;125:2011–7. [30] Bruins HM, Aben KKH, Arends TJ, van der Heijden AG, Witjes AJ.
2004;45:297–303. [36] Huo J, Ray-Zack MD, Shan Y, et al. Discerning patterns and quality of neoadjuvant chemotherapy use among patients with muscle-invasive bladder cancer. Eur Urol Oncol 2019;2:497–504. [37] Bryan RT, Evans T, Dunn JA, et al. A comparative analysis of the influence of gender, pathway delays, and risk factor exposures on the long-term outcomes of bladder cancer. Eur Urol Focus 2015;1:82–9.
The effect of the time interval between diagnosis of muscle-
[38] Nilbert M, Bläckberg M, Ceberg J, Hagberg O, Stenhoff R, Liedberg F.
invasive bladder cancer and radical cystectomy on staging and
Diagnostic pathway efficacy for urinary tract cancer: population-
survival: a Netherlands Cancer Registry analysis. Urol Oncol
based outcome of standardized evaluation for macroscopic hae-
2016;34:166, e1–6.
maturia. Scand J Urol 2018;52:237–43.
[31] Alva AS, Tallman CT, He C, et al. Efficient delivery of radical cystec-
[39] Hansen RP, Vedsted P, Sokolowski I, Søndergaard J, Olesen F. Time
tomy after neoadjuvant chemotherapy for muscle-invasive bladder
intervals from first symptom to treatment of cancer: a cohort study
cancer: a multidisciplinary approach. Cancer 2012;118:44–53. [32] Afshar M, Goodfellow H, Jackson-Spence F, et al. Centralisation of
of 2,212 newly diagnosed cancer patients BMC Health Services Research, Vol. 11. 2011.
radical cystectomies for bladder cancer in England, a decade on
[40] Bourgade V, Drouin SJ, Yates DR, et al. Impact of the length of time
from the ‘improving outcomes guidance’: the case for super cen-
between diagnosis and surgical removal of urologic neoplasms on
tralisation. BJU Int 2018;121:217–24. [33] Xia L, Taylor BL, Mamtani R, Christodouleas JP, Guzzo TJ. Associations between travel distance, hospital volume, and outcomes
survival. World J Urol 2014;32:475–9. [41] Wallace DMA, Bryan RT, Dunn JA, Begum G, Bathers S. Delay and survival in bladder cancer. BJU Int 2002;89:868–78.
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
available at www.sciencedirect.com journal homepage: euoncology.europeanurology.com
A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients Beth Russell a,*, Fredrik Liedberg b,c, Muhammad Shamim Khan d, Rajesh Nair d, Ramesh Thurairaja d, Sachin Malde d, Pardeep Kumar e, Richard T. Bryan f, Mieke Van Hemelrijck a a
Department of Translational Oncology and Urology Research, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK;
b
Department of Urology, Skåne University Hospital, Malmö, Sweden; c Institution of Translational Medicine, Lund University, Malmö, Sweden; d Department
of Urology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; e The Royal Marsden NHS Foundation Trust, London, UK; f Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Article info
Abstract
Article history: Received 16 July 2019Received in revised form 5 September 2019Accepted September 27, 2019
Context: The complexity of bladder cancer diagnosis and staging results in delays in definitive treatment of muscle-invasive bladder cancer by radical cystectomy. Objective: This systematic review and meta-analyses aim to assess the impact of delays in radical cystectomy. Evidence acquisition: A systematic review was conducted by searching Medline and Ovid Gateway using protocol-driven search terms in August 2019, with no time limit on the studies included. The identified studies were assessed according to strict criteria and using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist and Risk of Bias in Non-randomised Studies—of Interventions (ROBINS-I) tool. Meta-analyses were conducted based on the type of delay. Randomeffect models were used whereby the presence of a delay was the exposure variable and overall survival was the outcome of interest, for which pooled hazard ratios were calculated. Evidence synthesis: Nineteen studies were eligible for inclusion (17 532 patients), of which 10 were included in the meta-analyses. A longer delay between bladder cancer diagnosis and radical cystectomy resulted in a pooled hazard ratio of 1.34 (95% confidence interval [CI]: 1.18–1.53) for overall death. For a delay between transurethral resection and cystectomy, we found a pooled hazard ratio of 1.18 (95% CI: 0.99–1.41) for overall death. A pooled hazard ratio of 1.04 (95% CI: 0.93–1.16) was calculated for a longer delay between neoadjuvant chemotherapy and radical cystectomy. Conclusions: A delay in radical cystectomy after diagnosis was found to have a significantly detrimental effect on overall survival for bladder cancer patients. However, there was huge heterogeneity in how a delay was defined. Patient summary: In this review, we investigated the effect of a delay in radical treatment on survival. This review highlights the importance of scheduling radical cystectomies in a timely manner whilst monitoring factors such as comorbidities and scheduling, in order to treat patients requiring radical cystectomy without delay. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Gianluca Giannarini Keywords: Bladder cancer Radical cystectomy Delay Survival
* Corresponding author. Department of Translational Oncology and Urology Research, Research Oncology, King’s College London, 3rd Floor Bermondsey Wing, Guy’s Hospital, Great Maze Pond, London, UK. E-mail address: [email protected] (B. Russell).
https://doi.org/10.1016/j.euo.2019.09.008 2588-9311/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 2
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
1.
Introduction
Bladder cancer (BC) is the ninth most common cancer worldwide, with around 550 000 new cases in 2018 [1]. Five-year disease-specific survival rates are 77% in the USA and around 68% in Europe [2,3]. As many as 50% of muscle-invasive BC (MIBC) patients die from metastatic disease within 3 yr of diagnosis despite radical cystectomy (RC) [4]. A delay in radical treatment is thought to contribute to the risk of metastases and therefore decreased survival [5]. Thus, for selected patients with high-risk non– muscle-invasive BC (NMIBC) or MIBC who require RC as primary treatment, the European Association of Urology (EAU) recommends RC within 3 mo of diagnosis [6,7]. However, previous studies have demonstrated both increased and decreased survival associated with delay in RC. The impact of this delay on survival outcomes has recently been identified as one of the top 10 unanswered research questions by BC patients and health care professionals, thus highlighting the importance of studying this topic [8]. In addition to a delay between the first symptoms and a BC diagnosis, there are several mechanisms by which radical definitive treatment may be delayed for BC patients [9]. Patients may not be fit enough for immediate surgery and so require treatment of comorbidities, or may be referred from primary care physicians or urology units to different hospitals for surgery [10]. Furthermore, seeking a second opinion and the need for additional investigations, particularly up to the date of imaging, may also delay RC. The most recent systematic review of the effects of delays in RC was conducted by Fahmy et al [5] in 2006 and included 13 studies published between 1965 and 2006. Whilst they concluded that a delay in radical treatment was associated with a worse outcome, they did not quantify this effect. Given that the past 10 yr has seen a number of changes to the treatment of MIBC patients by RC (eg, centralisation of RC to larger hospitals, neoadjuvant chemotherapy [NAC], robotic cystectomy, and prehabilitation), we aimed to reassess this question by reviewing more recent studies, quantifying the effect of a delay on survival using meta-analyses, and establishing a standardised definition of a delay in radical treatment. 2.
Evidence acquisition
2.1.
Search strategy and inclusion criteria
The research question, search strategy, and inclusion and exclusion criteria were defined by a protocol (see the Supplementary material). Studies were identified by conducting searches of Medline (PubMed) and Ovid Gateway (Embase and Ovid) using the following search terms: “bladder” and/or “tumours” and/or “cancer”, “survival” or “death” and “delay” or “referral”. Initially, the titles of the studies were screened to identify the relevant studies. The abstracts and subsequently full texts were then carefully read to identify those that met the inclusion criteria. We used the following inclusion criteria: a randomised controlled study, an observational study, or an original
article (no commentaries, author’s replies, reviews, supplements, editorials, or systematic reviews), which was written in English, included patients who have undergone RC for BC, reported outcomes in the form of overall survival and/or BCspecific survival and/or 5-yr survival estimates, was certainly not looking at an alternative treatment regime to surgery, and definitely included at least one category of delay between diagnosis of BC and definitive treatment with RC. There were no criteria of selection based on the date of publication to include all results possible in the meta-analysis. Clinical characteristics, number of study participants, country of study, and delay definitions were extracted from each study. The search was carried out in August 2019. Screening of titles, abstracts, and full texts was carried out by B.R. and M.V.H. There were no disagreements between authors. B.R. extracted the data from the chosen articles. 2.2.
Meta-analyses
Studies were deemed suitable for inclusion in the metaanalysis if they reported both hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival as an outcome. The studies were categorised based on the type of delay investigated (total delay from diagnosis of BC to RC, delay between transurethral resection of bladder tumour [TURBT] and RC, and delay between termination of NAC and RC), and each category was meta-analysed separately. Randomeffect models were used whereby the presence of a delay was the exposure variable and overall survival was the outcome of interest (measured using the adjusted HRs from each study), for which pooled HRs were calculated. For each meta-analysis, sensitivity analyses were performed by removing each individual study, one at a time, to detect any changes in the overall result. I2 scores were also reported to define the severity of heterogeneity. 2.3.
Quality assessment of studies
All included studies were classified as observational; therefore, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 22-item checklist was used to assess the quality of the articles [11]. A risk of bias assessment was also carried out using the Risk of Bias in Non-randomised Studies—of Interventions (ROBINS-I) tool [12]. The review was also conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to enhance the quality of the results and was registered on PROSPERO (registration number: CRD42018118936). 2.4.
Evidence synthesis
Our search strategy identified 399 articles (Fig. 1). From these, 38 duplicates were excluded; a further 324 articles were excluded based on the inclusion criteria outlined above following title and abstract review. The full texts of 37 articles were then read, of which 19 were deemed suitable for inclusion (Table 1).
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
3
Fig. 1 – PRISMA flow diagram for selection of studies in systematic review and meta-analysis. NAC = neoadjuvant chemotherapy; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RC = radical cystectomy; TURBT = transurethral resection of bladder tumour.
All the remaining 19 articles were observational studies published between 1991 and 2019. The sample sizes ranged from ten to 2738, with a total of 17 532 patients who underwent RC in the studies. Eight of the studies were conducted in the USA, four in Canada, two in the UK, two in Germany, and one each in The Netherlands, Sweden, and New Zealand. 2.5.
Quality of studies
Assessment of each study using the STROBE checklist highlighted studies of particularly high or poor quality
(Supplementary Table 1). Most studies were of good quality according to the checklist; however, the studies by Munro et al [13] and Kahokehr et al [14] appeared to satisfy the fewest checklist items and, therefore, were deemed to have lower quality than the other studies. The studies by Gulliford et al [15], Williams et al [16], Santos et al [17], Mahmud et al [18], Kulkarni et al [19], Audenet et al [20], and Boeri et al [21] were considered to be of high quality. A risk of bias assessment revealed that all the studies were considered to have either a low or a moderate risk of bias (Supplementary Table 2) [12]. The impact of this variation was assessed through our leave one out sensitivity analyses
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 4
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Table 1 – Descriptive data of the studies included in the systematic review. Study ID
Reference
Authors (date of publication)
No. of participants who underwent RC and included in analysis
T stage
Pathological N stage
1 2 3 4 5 6 7 8 9
[22] [15] [16] [13] [23] [28] [14] [24] [20]
Lee et al (2006) Gulliford et al (1991) Williams et al (2017) Munro et al (2010) Gore et al (2009) Nielsen et al (2007) Kahokehr et al (2016) Liedberg et al (2005) Audenet et al (2019)
214 10 2738 96 441 592 43 141 2227
NA NA cT2-T4 NA cT2 cT2-T4 cT0-T4 cT0-T4 cT2-T4a
NX/N0/N+ NA NA NA N0 N0/N+ N0-N2 (clinical stage only) NX/N0/N+ cN0 pN0/N+
USA UK USA UK USA USA New Zealand Sweden USA
153 1782 1271 189 1633 1592 278 2397 1509 226
cT2-T4 cT2-T4 NA cT2-T4 NA NA NA NA cT2 cT2-T4
N0/N+ N0/N+ NA N0/N+ NA NA N0/N+ NX/N0/N+ N0 N0-N3
USA The Netherlands Canada Germany Canada Canada Germany Canada USA USA
Studies included in meta-analyses [31] Alva et al (2012) c 10 [30] Bruins et al (2016) b 11 [17] Santos et al (2015) a 12 13 [25] May et al (2004) a [26] Fahmy et al (2008) a 14 [18] Mahmud et al (2006) b 15 [27] Jager et al (2010) b 16 17 [19] Kulkarni et al (2009) b [29] Chu et al (2019) b,c 18 19 [21] Boeri et al (2019) c
Country of study
cT/cN = clinical T/N stage; NA = not applicable; NAC = neoadjuvant chemotherapy; RC = radical cystectomy; TURBT = transurethral resection of bladder tumour. Included in meta-analysis for total delay between diagnosis of bladder cancer and RC. b Included in meta-analysis for delay between TURBT and RC. c Included in meta-analysis for delay between NAC and RC. a
(see below). Furthermore, only six of the studies stated whether ethical approval or approval to use the respective databases was obtained. 2.6.
Delay and survival
The results from the 19 studies varied greatly, as did the methodology and therefore interpretation of the results. There was a variation in the type of delay investigated within the pathway from diagnosis of BC to RC (as shown in Tables 2 and 3). Ten of the studies evaluated the total delay between diagnosis of BC and RC, of which one included patients who received NAC [13,15–17,20,22–26]. Seven of the studies assessed the effect of the delay between TURBT and RC; all but one of these looked specifically at the most recent TURBT, whilst Jäger et al [27] analysed a delay in RC in the context of NMIBC and used the first TURBT as the start date for analysis [14,18,19,28–30]. Two of these studies carried out additional analyses for patients who received NAC. Two studies investigated only the delay between NAC and RC [21,31]. 2.7.
Delay between diagnosis of BC and RC
There was disparity in the number of days or months at which a significant association between delay and survival was identified (Tables 2 and 3). Several studies incorporated tumour stage into their analysis, and many concluded that this factor had a significant impact on the results. Overall, four of the studies found a significant association between delay from diagnosis to RC and survival (Tables 2 and 3) [17,22,23,26].
2.8.
Delay between TURBT and RC
Kulkarni et al [19] used cubic spline regression analysis to recommend an ideal wait time of 40 d. Audenet et al [20] first looked at the time from TURBT and RC as a continuous variable, and found no significant association with overall survival. They then looked at this time interval in deciles and concluded no significant cut-off point in predicting worse overall survival up to the ninth decile (222 d). Overall, four of the studies found an association between the delay in RC after TURBT and survival (Tables 2 and 3) [18,19,27,29]. 2.9.
Use of NAC
Five studies included separate analyses for patients who received NAC to determine whether a delay in time after NAC to RC is associated with survival [20,21,29,30]. Neither studies by Alva et al [31] or Bruins et al [30] found a significant association between a delay in RC after NAC and survival. Other studies included NAC patients in the overall analyses, but Kahokehr et al [14] looked at the time period between the last cycle of treatment and surgery and its effect on survival. This study concluded a paucity of significance between survival and delay when also including patients who received NAC. Chu et al [29] and Boeri et al [21] both investigated the time from the last documented infusion with NAC and RC. Both studies found that a longer delay between NAC and RC significantly increased the risk of overall death. Audenet et al [20] looked at the time from diagnosis to initiation of NAC and concluded that patients with a delay of 6 mo or more had significantly worse overall survival.
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 5
E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Table 2 – Delay definitions and summary of results for studies included in systematic review only. Study Reference ID
Authors (yr of publication)
Delay definition
Delay cut-off
Results
Median delay Delay between diagnosis of BC and RC [22] Lee et al (2006) 1
Conclusions
Diagnosis of BC to RC
93 d
61 d
Referral to 1 st treatment Diagnosis of BC to RC 1 st clinic to radiotherapy or RC Diagnosis of BC to RC
84 d
NA
84 d
NA
84 d
NA
28–56, 56–84, 84–168, & 168 d
NA
Diagnosis of BC to RC
60 d
49 d
TURBT to RC
90 d
55 d
No change in survival when there was a delay between the most recent TURBT and RC.
Studies that were also inclusive of NAC patients 7 [14] Kahokehr et al (2016) TURBT to RC
31 d
Mean = 62 d
From diagnosis to initiation of NAC: 56 d From diagnosis to RC: 183 d
From diagnosis to initiation of NAC: 39 d From initiation of NAC to RC: 112 d
No change in survival when there was a delay between TURBT and RC. No significant change in overall survival when there was an increase in time from diagnosis to surgery with or without the use of NAC. An increase in time from diagnosis to chemotherapy (56 d) was associated with an increased risk of pathological upstaging (OR = 1.27, 95% CI: 1.02–1.59).
2
[15]
Gulliford et al (1991)
3
[16]
Williams et al (2017)
4
[13]
Munro et al (2010)
5
[23]
Gore et al (2009)
8
[24]
Liedberg et al (2005)
Delay between TURBT and RC 6 [28] Nielsen et al (2007)
9
[20]
Audenet et al (2019)
Diagnosis of BC to RC
BC = bladder cancer; CI = confidence interval; NA = not TURBT = transurethral resection of bladder tumour.
2.10.
applicable;
Those delayed longer than 93 d were at a 96% increased risk of death from any cause and a 112% increased risk of death from BC compared with those with a cystectomy delay of 93 d. No change in survival when first treatment was delayed. No change in overall or cancer-specific survival when RC was delayed. No change in survival when radiotherapy or RC was delayed. A delay of >12 wk between diagnosis and RC was associated with a 201% increased risk of all-cause and disease-specific mortality (p = 0.003). No change in disease-specific survival when there was a delay between diagnosis and RC.
NAC = neoadjuvant
Reasons for delays
Several studies included reasons as to why treatment with RC was delayed. The studies by Lee et al [22] and Alva et al [31] suggested that scheduling was one of the main causes for delay in surgical treatment, with as many as 46% of the cohort in the study by Lee et al [22] were affected by this. Other causes included seeking multiple medical opinions, social issues, and misdiagnosis. Both Lee et al [22] and Gore et al [23] suggested that reluctance to treat and patients’ comorbidities also contributed to delays, with two other studies also reaching the same conclusion. According to Gore et al [23], comorbidities affected the delay since patients had to wait to be transferred to centres better equipped to deal with the burden of care, as well as requiring more time for medical optimisation. Chu et al [29] ran a separate logistic regression analysis to identify factors affecting whether the patients experienced a delay or not. They concluded that living in a highpoverty neighbourhood or rural area, and being transferred to another care provider between TURBT and RC were
chemotherapy;
OR = odds
ratio;
RC = radical
cystectomy;
associated with increased RC delays. Conversely, no patient, provider, or health system factors were found to be independently associated with RC delays in the NAC cohort. Boeri et al [21] also looked into factors associated with a delay and found that patients with a higher Charlson Comorbidity Index (1) were associated with longer median time to cystectomy. 2.11.
Gender disparities
Most of the studies investigated gender in terms of the varying delays experienced by patients and/or how survival was affected by delay between genders. Fahmy et al [26] additionally found a significant association with an increased median delay (defined as the period between visiting a family practitioner and seeing a urologist) in women when compared with men. They also concluded that men were more likely to experience a delay of <20 d than women for the same time period. In contrast, Chu et al [29] identified male gender as an independent characteristic associated with RC delays.
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 6
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Table 3 – Delay definitions and summary of results for studies included in the meta-analyses. Study ID Reference
Authors (yr of publication)
Delay definition
Delay cut-offa
Results Median delay
Delay between diagnosis of BC and RC [17] Santos et al (2015) 12
Diagnosis of BC to RC (including referral delay)
Direct/indirect referral
30 d
13
[25]
May et al (2004)
Diagnosis of BC to RC 90 d
55 d
14
[26]
Fahmy et al (2008)
Diagnosis of BC to RC 24, 24–84, 85 d
93 d
Delay between TURBT and RC [18] Mahmud et al (2006) TURBT to RC 15
84 d
33 d
16
[27]
Jager et al (2010)
TURBT to RC
120 d
122 d
17
[19]
Kulkarni et al (2009)
TURBT to RC
90 d
50 d
18
[29]
Chu et al (2019)
TURBT to RC
From TURBT to RC: 84 d
NA
11
[30]
Bruins et al (2016)
TURBT to RC
60 d
No NAC: 50 d NAC: 133 d
NAC to RC
28–84 d
From initiation of NAC: 117 d From termination of NAC: 49 d 53 d
Delay between NAC and RC 10 [31] Alva et al (2012)
19
[21]
Boeri et al (2019)
NAC to RC
70 d
18
[29]
Chu et al (2019)
TURBT to RC and NAC to RC
From completion of NA NAC to RC: 77 d
Conclusions
Patients indirectly referred to a urologist after a first GP visit experienced a 29% increased risk of mortality compared with those directly referred (95% CI: 1.10–1.52). No change in overall survival when RC was delayed, though this relationship was borderline significant (HR = 1.62, 95% CI: 0.99–2.66). A delay of <25 or >84 d between visiting the family physician and RC was associated with a 230% and a 40% increased risk of death from any cause, respectively (95% CI: 1.4–3.9 and 1.1–1.8, respectively). A delay of >12 wk between the most recent TURBT and RC is associated with a 20% increased risk of dying from any cause (95% CI: 1.00–1.50). A delay of >120 d between the first TURBT and RC was associated with significantly worse 5-yr cancer-specific survival compared with those with a delay of <120 d (77% vs 86%). A delay of >90 d between TURBT and RC was associated with an increased risk of death from all causes compared with those with a delay of 90 d (HR = 1.001, 95% CI: 1.000– 1.002). This represents an increased risk of death for each day a patient waits for an RC. Overall survival was significantly reduced in patients who did not receive NAC and were aged <80 yr (HR: 1.39, p < 0.05). No change in survival when there was a delay between diagnosis of BC and RC. No change in survival when there was a delay between the termination of NAC treatment and RC or between the initiation of NAC and RC. Time to cystectomy of >10 wk was associated with adverse overall survival and bladder cancer–specific survival. Patients who received NAC and whose RC was delayed suffered significantly higher mortality over time.
BC = bladder cancer; CI = confidence interval; GP = general physicians; HR = hazard ratio; NA = not applicable; NAC = neoadjuvant chemotherapy; RC = radical cystectomy; TURBT = transurethral resection of the bladder tumour. a The cut-off point for each study is the one from which the HRs and 95% CIs were taken for the meta-analyses.
2.12.
Meta-analyses
The delay definitions for each study are outlined in Fig. 2, and these were considered the exposure variables in the meta-analyses. When studying the delay between diagnosis of BC and RC, the meta-analysis revealed a pooled HR of 1.34 (95% CI: 1.18–1.53) for overall survival (Fig. 3). Sensitivity analyses by the removal of individual studies did not identify any significant changes in the results. The I2 test was 0.0%, suggesting a very low level of heterogeneity between the studies. For a delay between TURBT and RC, the meta-analysis calculated a pooled HR of 1.18 (95% CI: 0.99–1.41) for overall survival (Fig. 3). The removal of
individual studies in the sensitivity analyses did not significantly change the overall result for all studies except for the study by Kulkarni et al [19]. Removal of this study resulted in a pooled HR of 1.26 (95% CI: 1.06–1.51). The I2 test was 72.9%, indicating a relatively high level of heterogeneity between the studies. For a delay between NAC and RC, the meta-analysis calculated an HR of 1.04 (95% CI: 0.93-1.16) for overall survival (Fig. 3). Sensitivity analyses by the removal of individual studies did not identify any significant changes in the results. The funnel plots for the meta-analyses appear to suggest a slight publication bias in the direction of worse survival associated with a delay (Supplementary Fig. 1).
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Fig. 2 – Definitions for total delay (diagnosis of BC to RC) and delay between TURBT and RC. (A) The number of days used by each study to define a total delay in patients receiving treatment by radical cystectomy. The study by Santos et al [17] is not included, as the delay was defined as “direct” or “indirect” referral, and was therefore not able to be depicted on the diagram. (B) The number of days used by each study to define a delay between TURBT and RC. The study by Kulkarni et al [19] is not included in the diagram, as delay was treated as a continuous variable. (C) The number of days used by each study to define a delay between NAC and RC. The study by Alva et al [31] is not included in the diagram, as delay was treated as a continuous variable. BC = bladder cancer; NAC = neoadjuvant chemotherapy; RC = radical cystectomy; TURBT = transurethral resection of bladder tumour.
3.
Discussion
This is the first study to estimate the pooled effect on survival from a delay in RC using results from multiple
7
studies. Our findings suggest that a longer period of time between diagnosing BC and undergoing RC negatively impacts the overall survival of patients and is influenced by many factors. This review also highlights that despite the 12-wk EAU guideline, many centres do not adhere to this and/or choose to analyse their data using different cut-offs. We, therefore, need to work out a safe cut-off and ensure that there is a consensus in how delay is defined. Whilst the pooled meta-analysis for a delay between TURBT and RC was not significant, removal of the study by Kulkarni et al [19] resulted in a significant result. Interestingly, Kulkarni et al [19] treated delay as a continuous variable, which may be a contributing factor to the reasons why this result varied from the others. The previous systematic review conducted by Fahmy and colleagues [5] concluded that the majority of studies confirmed that delays were associated with worse outcomes. Similar to the current study, Fahmy and colleagues [5] found that there was a variation in the type of delay investigated and the period of time used to define a delay. A major advantage of the current study compared with the previous review is the inclusion of meta-analyses to quantify the impact that delays in RC may have on overall survival. Furthermore, most of the studies included were published after 2006, therefore incorporating data that were not available at the time of the previous review. Comorbidities, scheduling delays, and reluctance to be treated were all suggested as substantial contributors to treatment delay [14,17,22,23]. Of these three factors, scheduling delays should be both manageable and avoidable. However, the so-called “distance bias effect”, suggesting improved survival for patients referred to a distant higher-volume hospital for RC [32], also generates prolonged treatment delay—“a volume delay paradox” that needs to be handled in clinical practice [33]. Nevertheless, awareness of this phenomenon could still motivate hospitals to have patients treated in a timely manner and subsequently improve outcomes. Comorbidities and reluctance to treat are much harder variables to manage; it is crucial that clinicians are aware of their impact on treatment delay and, hence, survival. Accessible patient information and signposting to peer support groups can help patients address their reluctance to be treated, by allowing them to receive encouragement and information directly from other people who have had an RC. Administering NAC to improve survival after RC also adds complexity to the scheduling process before RC, and delays in the start of such preoperative chemotherapy by more than 8 wk have been associated with pathological upstaging [20]. The studies included in this review found mixed results between a delay in RC and survival in patients who received NAC, with the meta-analysis finding no significant association. It is known that NAC prior to RC significantly reduces patient mortality [34,35]; however, from the current data, it is not possible to identify whether the lack of an effect of delay on mortality in those who received NAC is due to the potential beneficial effects of NAC. Furthermore, patients who receive NAC tend to be younger with fewer comorbidities and are therefore already at a survival advantage [36].
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 8
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Fig. 3 – Forest plots. (A) Forest plot for total delay between diagnosis of bladder cancer and radical cystectomy. (B) Forest plot for delay from TURBT to RC. (C) Forest plot for delay between termination of NAC and radical cystectomy. CI = confidence interval; HR = hazard ratio; NAC = neoadjuvant chemotherapy; RC = radical cystectomy; TURBT = transurethral resection of the bladder tumour.
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Most of the studies investigating disparities in delay time and/or survival amongst men and women did not find any significant association. This suggests that both males and females are equally as likely to experience a delay and are both similarly affected by delays in RC; although delays in the referral of symptomatic female patients from primary care to secondary care may contribute to a stage migration at eventual diagnosis, there is no such disparity in secondary care [37]. Some studies (eg, those by Gulliford et al [15] and Munro et al [13]) did not limit their exposure to include only RC, and additionally included radical radiotherapy and systemic chemotherapy as treatment options. Therefore, we could not be certain that the delays associated with the risk of survival were accurate for delays in RC, and these studies were subsequently excluded from the meta-analysis. Despite the 3-mo guideline set by the EAU, it is clear from this review that not all centres are adhering to this guideline and many of the studies available use varied cut-off points for their analysis. There is also uncertainty as to the definition of the starting point for delay, for example, at onset of symptoms, at diagnosis, at initial TURBT, or after termination of NAC. For example, the 40 d suggested by Kulkarni et al [19] refers to the delay between TURBT and cystectomy in an era before NAC was widespread. However, the development of rapid access diagnostic pathways for patients with macroscopic haematuria strongly suggest the haematuria referral date as the starting point for delay and facilitate national guideline recommendations on treatment delay [38]. Across all malignancies, BC patients experience the longest delays from symptom onset to diagnosis [39], and it is therefore advisable to strive toward a short delay between haematuria clinic assessment and RC (especially when one considers the psychological effects of delaying RC) [40]. Equally, one may also argue that the first TURBT date is a clear, measureable time point to start timing a delay from. However, the results from this study suggest that a longer delay from this time point may not impact delay significantly. Possible reasons for this may be the debulking of the tumour during the procedure or the variation in the cut-offs used to define a delay. 4.
Strengths and limitations
Many of the studies included were large cohort studies that could generally be considered to have high external validity. However, the data used for the study by Alva and colleagues [31] were obtained from a single centre and, consequently, as stated by the authors, are limited in terms of generalisability. Tumour stage was found to be a major influential factor for prognosis and was included in most study analyses. However, the study by Santos et al [17] did not adjust for stage, which is a major limitation of this study. Alternatively, patients with more advanced tumour stages might be prioritised in scheduling ahead of patients with less advanced asymptomatic tumours [37,41]; thus, tumour stage might affect the exposure variable in cohort studies
9
investigating treatment delays. Chu et al [29] additionally identified positive lymph node status as a strong predictor of increased mortality amongst patients who received NAC. Therefore, studies that failed to report pathological N stage are limited. This review did not acquire enough studies to be able to perform subgroup analyses by N or T stage. As mentioned, these variables can have an impact on survival; therefore, this is a limitation to the current meta-analyses. Another limitation is the paucity of data for fundamental variables in some studies; for example, Nielsen et al [28] did not collect information on pre-existing comorbidities, potentially major contributory factors to prolonged delays. The most prominent limitation in this review was the heterogeneity between studies due to the variation in the definition of delay, as well as the demographic composition of the cohorts and the endpoints of interest. This made comparing these different studies challenging (as noted by Mahmud et al [18]). The heterogeneity of the studies is highlighted in the relatively large I2 scores reported for the meta-analyses. 5.
Future research
Results from these studies have shed light on the complexity of the relationship between RC delays and survival. We therefore recommend that future studies consider this complexity when planning data capture. In the setting of the guideline-recommended treatment of NAC and RC, we recommend the following definitions for periods of delay to be used by future studies:
1 Symptom onset to primary care referral for urological assessment 2 Referral for urological assessment to actual urological assessment 3 Initial urological assessment to TURBT 4 TURBT to commencement of NAC 5 Commencement of NAC to completion of NAC 6 Completion of NAC to RC Not all studies will be established to capture all time points, but the relevant components thereof are to be recommended. Furthermore, awareness of all the components of total delay may highlight individual elements where pathways can be improved and/or optimised. 6.
Conclusions
This systematic review has updated the data and knowledge regarding delays in RC and patient survival, whilst the addition of the meta-analysis enabled quantification of this pooled effect for the first time. The BC diagnostic and treatment pathway is complex, involving generally elderly patients with multiple comorbidities; hence, some delays may be unavoidable. However, there still remains a lack of consensus as to what period of delay is acceptable before negatively impacting survival; hence, more work is needed to
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 10
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
answer what has recently been identified as one of the top 10 unanswered questions in BC. Notwithstanding, we have demonstrated that a longer delay from BC diagnosis to RC is associated with significantly worse survival. This current review has also highlighted the lack of standardisation regarding how delays are defined, and therefore using more fixed, measurable time points is of interest for future studies. In conclusion, BC patients who require RC should be treated without delay so as to maximise survival. Several factors impact delay, such as other medical conditions and scheduling, and these must be monitored by medical practitioners in order to minimise unnecessary delays and maximise survival.
[5] Fahmy NM, Mahmud S, Aprikian AG. Delay in the surgical treatment of bladder cancer and survival: systematic review of the literature. Eur Urol 2006;50:1176–82. [6] Babjuk M, Böhle A, Burger M, et al. Guidelines on non-muscleinvasive bladder cancer (Ta, T1 and CIS). European Association of Urology 2015. [7] Witjes J, Bruins M, Cathomas R, et al. EAU guidelines: muscleinvasive and metastatic bladder cancer.
https://uroweb.org/
guideline/bladder-cancer-muscle-invasive-and-metastatic/#72019 [8] Bessa A, Maclennan S, Enting D, et al. Consensus in bladder cancer research priorities between patients and healthcare professionals using a four-stage modified Delphi method. Eur Urol 2019;76:258–9. [9] Williams SB, Hudgins HK, Ray-zack MD, et al. Systematic review of factors associated with the utilization of radical cystectomy for
Author contributions: Beth Russell had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
bladder cancer. Eur Urol Oncol 2019;2:119–25. [10] Tomaszewski JJ, Handorf E, Corcoran AT, et al. Care transitions between hospitals are associated with treatment delay for patients with muscle invasive bladder cancer. J Urol 2014;192:1349–54.
Study concept and design: Russell, Van Hemelrijck.
[11] Vandenbroucke JP, Von Elm E, Altman DG, et al. Strengthening the
Acquisition of data: Russell.
Reporting of Observational Studies in Epidemiology (STROBE):
Analysis and interpretation of data: Russell, Van Hemelrijck.
explanation and elaboration. Epidemiology 2007;18:805–35.
Drafting of the manuscript: Russell. Critical revision of the manuscript for important intellectual content: Russell, Liedberg, Khan, Nair, Thurairaja, Malde, Kumar, Bryan, Van Hemelrijck.
[12] Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:i4919. [13] Munro NP, Sundaram SK, Weston PMT, et al. A 10-year retrospective
Statistical analysis: Russell.
review of a nonrandomized cohort of 458 patients undergoing
Obtaining funding: Van Hemelrijck, Kumar.
radical radiotherapy or cystectomy in Yorkshire, UK. Int J Radiat
Administrative, technical, or material support: Van Hemelrijck.
Oncol 2010;77:119–24.
Supervision: Van Hemelrijck, Liedberg, Bryan. Other: None.
[14] Kahokehr A, Glasson J, Studd R. Surgical waiting time for radical cystectomy: a New Zealand experience. ANZ J Surg 2016;86:1042–5. [15] Gulliford MC, Petruckevitch A, Burney PGJ. Survival with bladder
Financial disclosures: Beth Russell certifies that all conflicts of interest,
cancer, evaluation of delay in treatment, type of surgeon, and
including specific financial interests and relationships and affiliations
modality of treatment. BMJ 1991;303:437–40.
relevant to the subject matter or materials discussed in the manuscript
[16] Williams SB, Huo J, Dafashy TJ, et al. Survival differences among
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
patients with bladder cancer according to sex: Critical evaluation of
stock ownership or options, expert testimony, royalties, or patents filed,
radical cystectomy use and delay to treatment. Urol Oncol Semin
received, or pending), are the following: None.
Orig Investig 2017;35:602, e1–9.
Funding/Support and role of the sponsor: This work was supported by Guy’s and St Thomas’ Charity, and the Royal Marsden Cancer Charity. Acknowledgements: We would like to thank Fight Bladder Cancer for its support and input into this review.
[17] Santos F, Dragomir A, Kassouf W, Franco E, Aprikian A. Urologist referral delay and its impact on survival after radical cystectomy for bladder cancer. Curr Oncol 2015;22:e20–6. [18] Mahmud SM, Fong B, Fahmy N, Tanguay S, Aprikian AG. Effect of preoperative delay on survival in patients with bladder cancer undergoing cystectomy in Quebec: a population based study. J Urol 2006;175:78–83.
Appendix A. Supplementary data
[19] Kulkarni GS, Urbach DR, Austin PC, Fleshner NE, Laupacis A. Longer wait times increase overall mortality in patients with bladder
Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j. euo.2019.09.008.
cancer. J Urol 2009;182:1318–24. [20] Audenet F, Sfakianos JP, Waingankar N, et al. A delay 8 weeks to neoadjuvant chemotherapy before radical cystectomy increases the risk of upstaging. Urol Oncol Semin Orig Investig 2019;37:116–22. [21] Boeri L, Soligo M, Frank I, et al. Delaying radical cystectomy after neoadjuvant chemotherapy for muscle-invasive bladder cancer is
References
associated with adverse survival outcomes. Eur Urol Oncol [1] World Cancer Research Fund. Bladder cancer statistics. https:// www.wcrf.org/dietandcancer/cancer-trends/ bladder-cancer-statistics2018 [2] European Network of Cancer Registries. Bladder cancer (BLC) factsheet.
https://www.encr.eu/sites/default/files/factsheets/
ENCR_Factcheet_Bladder_Cancer_2016.pdf2016 [3] American Cancer Society. Survival rates for bladder cancer. https:// www.cancer.org/cancer/bladder-cancer/ detection-diagnosis-staging/survival-rates.html2016 [4] Wu X-R. Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 2005;5:713–25.
2019;2:390–6. [22] Lee CT, Madii R, Daignault S, et al. Cystectomy delay more than 3 months from initial bladder cancer diagnosis results in decreased disease specific and overall survival. J Urol 2006;175:1262–7. [23] Gore JL, Lai J, Setodji CM, Litwin MS, Saigal CS. Mortality increases when radical cystectomy is delayed more than 12 weeks: results from a SEER Medicare analysis. Cancer 2009;115:988–96. [24] Liedberg F, Anderson H, Mansson W. Treatment delay and prognosis in invasive bladder cancer. J Urol 2005;174:1777–81. [25] May M, Nitzke T, Helke C, Vogler H, Hoschke B. Significance of the time period between diagnosis of muscle invasion and radical
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008
EUO-283; No. of Pages 11 E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
cystectomy with regard to the prognosis of transitional cell carcinoma of the urothelium in the bladder. Scand J Urol Nephrol 2004;38:231–5. [26] Fahmy N, Kassouf W, Jeyaganth S, et al. An analysis of preoperative delays prior to radical cystectomy for bladder cancer in Quebec. CUAJ 2008;2:102–8.
11
following radical cystectomy in patients with muscle-invasive bladder cancer. Urology 2018;114:87–94. [34] Advanced Bladder Cancer Overview Collaboration. Neoadjuvant chemotherapy for invasive bladder cancer. Cochrane Database Syst Rev 2005;2:CD005246. [35] Sherif A, Holmberg L, Rintala E, et al. Neoadjuvant cisplatinum
[27] Jäger W, Thomas C, Haag S, et al. Early vs delayed radical cystectomy
based combination chemotherapy in patients with invasive bladder
for “high-risk” carcinoma not invading bladder muscle: delay of
cancer: a combined analysis of two Nordic studies. Eur Urol
cystectomy reduces cancer-specific survival. BJU Int 2011;108(8 Pt 2), E284–8. [28] Nielsen ME, Palapattu GS, Karakiewicz PI, et al. A delay in radical cystectomy of &3 months is not associated with a worse clinical outcome. BJU Int 2007;100:1015–20. [29] Chu AT, Holt SK, Wright JL, et al. Delays in radical cystectomy for muscle-invasive bladder cancer. Cancer 2019;125:2011–7. [30] Bruins HM, Aben KKH, Arends TJ, van der Heijden AG, Witjes AJ.
2004;45:297–303. [36] Huo J, Ray-Zack MD, Shan Y, et al. Discerning patterns and quality of neoadjuvant chemotherapy use among patients with muscle-invasive bladder cancer. Eur Urol Oncol 2019;2:497–504. [37] Bryan RT, Evans T, Dunn JA, et al. A comparative analysis of the influence of gender, pathway delays, and risk factor exposures on the long-term outcomes of bladder cancer. Eur Urol Focus 2015;1:82–9.
The effect of the time interval between diagnosis of muscle-
[38] Nilbert M, Bläckberg M, Ceberg J, Hagberg O, Stenhoff R, Liedberg F.
invasive bladder cancer and radical cystectomy on staging and
Diagnostic pathway efficacy for urinary tract cancer: population-
survival: a Netherlands Cancer Registry analysis. Urol Oncol
based outcome of standardized evaluation for macroscopic hae-
2016;34:166, e1–6.
maturia. Scand J Urol 2018;52:237–43.
[31] Alva AS, Tallman CT, He C, et al. Efficient delivery of radical cystec-
[39] Hansen RP, Vedsted P, Sokolowski I, Søndergaard J, Olesen F. Time
tomy after neoadjuvant chemotherapy for muscle-invasive bladder
intervals from first symptom to treatment of cancer: a cohort study
cancer: a multidisciplinary approach. Cancer 2012;118:44–53. [32] Afshar M, Goodfellow H, Jackson-Spence F, et al. Centralisation of
of 2,212 newly diagnosed cancer patients BMC Health Services Research, Vol. 11. 2011.
radical cystectomies for bladder cancer in England, a decade on
[40] Bourgade V, Drouin SJ, Yates DR, et al. Impact of the length of time
from the ‘improving outcomes guidance’: the case for super cen-
between diagnosis and surgical removal of urologic neoplasms on
tralisation. BJU Int 2018;121:217–24. [33] Xia L, Taylor BL, Mamtani R, Christodouleas JP, Guzzo TJ. Associations between travel distance, hospital volume, and outcomes
survival. World J Urol 2014;32:475–9. [41] Wallace DMA, Bryan RT, Dunn JA, Begum G, Bathers S. Delay and survival in bladder cancer. BJU Int 2002;89:868–78.
Please cite this article in press as: Russell B, et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.09.008